Not so useless after all: even “gene deserts” have oases

Huge "gene deserts" DNA don't code for proteins. Can they do anything? New …

As researchers sequenced the genomes of mammals, they came across large regions that didn't seem to contain any protein-coding genes. These "gene deserts" often stretched for thousands of DNA base pairs (called kilobases), and their discovery left researchers arguing about whether they served any function.

One hint that these deserts might be important was the finding that a gene desert on the short arm of chromosome 9 contains some DNA base differences (single nucleotide polymorphisms, or SNPs) associated with coronary artery disease; others were associated with type 2 diabetes.

The desert runs for almost 200 kilobases. Since there were no real genes nearby, it was unclear exactly how these desert SNPs could manifest themselves as disease. A recent study by Kelly Frazer and colleagues at UCSD, published in Nature, may provide a clue: there are 33 genetic control elements in the desert region.

These control elements are called "enhancers." They are regions of DNA to which proteins bind in a sequence-specific manner; this binding enhances the activity of genes on the same chromosome. An enhancer sequence does not need to be close to the gene it acts upon; it is brought into physical proximity with its target gene through the geometric conformation of the chromosome.

The SNP most consistently associated with coronary artery disease is located in a STAT-1 binding site. STAT-1 is a protein that mediates the inflammatory response and is associated with angiogenesis and atherosclerosis. When cells that have one copy of the risk-associated SNP are treated with a pro-inflammation factor called interferon-γ, STAT-1 binds to the site. However, in cell lines homozygous for the risk SNP, STAT-1 failed to bind to its site. (The risk haplotype confers a two-fold greater risk of heart attack to Caucasians who carry it.)

To determine which genes are affected by these newly found enhancers, the researchers looked at all of the genes located within 2 megabases (millions of bases) of the desert region. There are twenty genes upstream and one downstream, and researchers used a new technique to study long range genetic interactions, called chromatin conformation capture (or 3C). In 3C, interacting regions of DNA, along with any proteins bound there, are chemically linked, and then excess DNA is cut away.

3C showed that the enhancers interacted with four nearby genes, and researchers confirmed these interactions with more traditional techniques. Interestingly, the association between the enhancers and the three genes implicated in coronary artery disease was modulated by interferon-γ.

This study thus validated a relatively new technique, 3C; defined a link between genetic susceptibility to heart disease and inflammation; and demonstrated how genome wide association studies can be used to find novel genetic elements with clinical importance.